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3-1-2013

Melanopsin, photosensitive ganglion cells, andseasonal affective disorder.Kathryn A Roecklein

Patricia M Wong

Megan A Miller

Shannon D Donofry

Marissa L Kamarck

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Recommended CitationRoecklein, Kathryn A; Wong, Patricia M; Miller, Megan A; Donofry, Shannon D; Kamarck, MarissaL; and Brainard, George C, "Melanopsin, photosensitive ganglion cells, and seasonal affectivedisorder." (2013). Department of Neurology Faculty Papers. Paper 66.http://jdc.jefferson.edu/neurologyfp/66

AuthorsKathryn A Roecklein, Patricia M Wong, Megan A Miller, Shannon D Donofry, Marissa L Kamarck, andGeorge C Brainard

This article is available at Jefferson Digital Commons: http://jdc.jefferson.edu/neurologyfp/66

Neuroscience and Biobehavioral Reviews 37 (2013) 229–239

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rna l h omepa ge: www.elsev ier .com/ locate /neubiorev

Review

Melanopsin, photosensitive ganglion cells, and seasonal affective disorder�

Kathryn A. Roeckleina,∗, Patricia M. Wonga, Megan A. Millera, Shannon D. Donofrya,Marissa L. Kamarcka, George C. Brainardb

a Department of Psychology, University of Pittsburgh, 3500 Sennott Square, 210 South Bouquet St., Pittsburgh, PA 15260, USAb Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA

a r t i c l e i n f o

Article history:Received 10 July 2012Received in revised form 5 November 2012Accepted 21 December 2012

Keywords:DepressionRetinohyopothalamic pathwayMelanopsinSleepSeasonal affective disorderPhotosensitive retinal ganglion cells

a b s t r a c t

In two recent reports, melanopsin gene variations were associated with seasonal affective disorder (SAD),and in changes in the timing of sleep and activity in healthy individuals. New studies have deepened ourunderstanding of the retinohypothalamic tract, which translates environmental light received by theretina into neural signals sent to a set of nonvisual nuclei in the brain that are responsible for functionsother than sight including circadian, neuroendocrine and neurobehavioral regulation. Because this path-way mediates seasonal changes in physiology, behavior, and mood, individual variations in the pathwaymay explain why approximately 1–2% of the North American population develops mood disorders witha seasonal pattern (i.e., Major Depressive and Bipolar Disorders with a seasonal pattern, also known asseasonal affective disorder/SAD). Components of depression including mood changes, sleep patterns,appetite, and cognitive performance can be affected by the biological and behavioral responses to light.Specifically, variations in the gene sequence for the retinal photopigment, melanopsin, may be respon-sible for significant increased risk for mood disorders with a seasonal pattern, and may do so by leadingto changes in activity and sleep timing in winter. The retinal sensitivity of SAD is hypothesized to bedecreased compared to controls, and that further decrements in winter light levels may combine to trig-ger depression in winter. Here we outline steps for new research to address the possible role of melanopsinin seasonal affective disorder including chromatic pupillometry designed to measure the sensitivity ofmelanopsin containing retinal ganglion cells.

© 2013 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2301.1. Circadian, neuroendocrine and neurobehavioral responses to light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2301.2. Gene variations and human behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2301.3. Functions of melanopsin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

1.3.1. Pupillometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311.3.2. Circadian photoentrainment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311.3.3. Melatonin synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2321.3.4. Circannual rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2321.3.5. Sleep regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2321.3.6. Alertness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2321.3.7. Daily rhythm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

2. SAD etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2322.1. Circadian hypotheses of SAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

2.1.1. Phase shift hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2332.1.2. Photoperiod . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2332.1.3. Retinal sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2332.1.4. Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

� OMIM ID: 606665.∗ Corresponding author. Tel.: +1 412 624 4553; fax: +1 412 648 2002.

E-mail addresses: kroeck@pitt.edu, kroecklein@gmail.com (K.A. Roecklein).

0149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.neubiorev.2012.12.009

230 K.A. Roecklein et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 229–239

2.1.5. Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2342.1.6. Hyperphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2342.1.7. Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

2.2. Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2342.3. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

3. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2353.1. Methodological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2353.2. Chromatic pupillometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2353.3. Assessment timing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2363.4. Blue light hazard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2363.5. Optimizing light therapy for SAD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2363.6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

1. Introduction

The recently described melanopsin light input pathway maycontribute to our understanding of seasonal affective disorder(SAD). SAD involves recurrent depressive episodes in the fall orwinter months with remission or a change to mania or hypomaniain the spring (Rosenthal et al., 1984). SAD is common and perva-sive, affecting 0.8–2.2% of the North American population (Lam andLevitt, 1999). Three evidence-based treatments exist (i.e., antide-pressant medications, light therapy, and psychotherapy), but notall SAD patients respond fully to these treatments. Incorporatingresearch on melanopsin has the potential to improve our under-standing of the etiology of SAD by identifying a link between genevariations, biomarkers, and risk for depression, and also to suggestnew and individually tailored treatments.

The role of melanopsin in SAD has not been thoroughly explored,although the rationale for further investigation is strong. The reg-ular winter recurrence of episodes, seasonal biological changes,and the benefit of light therapy for SAD suggest that its etiologyis rooted in abnormal responses to light. Shorter photoperiods inwinter may trigger SAD in susceptible individuals, analogous toother mammalian seasonal responses. An abnormal response tolight may be mediated by abnormal retinal signaling (Wehr et al.,2001), termed the retinal subsensitivity hypothesis of SAD (Hebertet al., 2002). Such hypotheses were conceived prior to the descrip-tion of melanopsin and its role in circadian, neuroendocrine andneurobehavioral processes. Abnormal retinal responses to lightcould be due to differences in the retinohypothalamic pathway,comprised of retinal ganglion cells that contain the photosensitiveprotein melanopsin. Some SAD patients differ from controls basedon sequence variation in the melanopsin gene (Roecklein et al.,2009). Additionally, those variations are associated with seasonalchanges in sleep timing and chronotype (Roecklein et al., 2012).Although melanopsin variations may hypothetically be the physio-logical basis underlying the retinal subsensitivity hypothesis, otherpossibilities are discussed as well.

Below, we briefly summarize the neurobiology and functionof the melanopsin system, which has recently been reviewedby others (e.g., Do and Yau, 2010). Although the implications ofthe melanopsin system for human eye disease and human sleepand cognitive performance have been described elsewhere (e.g.,Kawasaki and Kardon, 2007), this review focuses on the potentialrole of melanopsin in SAD and possible treatment implications.

1.1. Circadian, neuroendocrine and neurobehavioral responses tolight

The discovery of melanopsin confirmed that rods and cones arenot the only photoreceptors involved in circadian, neuroendocrine,and neurobehavioral responses to light (Provencio et al., 1998).

Melanopsin is found in intrinsically photosensitive retinal ganglioncells (ipRGCs), which are photosensitive even when input from rodsand cones is pharmacologically blocked (Berson et al., 2002; Hattaret al., 2002; Gooley et al., 2001). Although melanopsin is foundin only 2% of ganglion cells, their dendrites form a “photorecep-tive net” across the retina (Berson et al., 2002; Hattar et al., 2002;Gooley et al., 2001; Provencio et al., 2002). Additionally, melanopsincell responses increase with light intensity with a high threshold,and they are slow to initiate and terminate nerve impulses, qual-ities making them ideal for measuring gross environmental lightlevels rather than forming crisp images (Berson et al., 2002, 2010;Dacey et al., 2005; Pu, 2000). Melanopsin signaling pathways, asestablished in animal models, have complex inputs from bipolar,amacrine, rod, and cone cells, and multiple projections (Do and Yau,2010). If conserved in humans, the retinorecipient areas that maybe important in SAD include the suprachiasmatic nucleus (SCN) andintergeniculate leaflet (circadian regulation), the lateral hypothala-mus (energy homeostasis), and the ventral subparaventricular zoneand preoptic nucleus (sleep promotion and regulation; Grahamet al., 2008; Hannibal and Fahrenkrug, 2004; Hattar et al., 2002,2006).

1.2. Gene variations and human behavior

We have reported melanopsin gene (OPN4) associations in twopopulations. In a study of 220 individuals, those with the TTgenotype at P10L (rs2675703) had a 5.6 times increased risk ofSAD (Roecklein et al., 2009). This association was retested in ahealthy sample to remove the effect of mood disorder symptoms.In 268 healthy individuals, the effects of P10L TT genotype and daylength interacted to predict earlier bedtime when individuals wereassessed on shorter days, and later bedtime when individuals wereassessed on longer days (Roecklein et al., 2012). If replicated, andfound in SAD as well, these data may indicate a specific etiologi-cal relationship between P10L, changes in sleep timing, and SAD.To date, however, these are the only two SNP-association studiesshowing a link between melanopsin and SAD in the first study, andbetween melanopsin and seasonal changes in sleep timing in thesecond study. Replication, and other studies designed to evaluatethe role of melanopsin in SAD are needed. Such studies will greatlybenefit from the basic science literature describing the functions ofmelanopsin and melanopsin containing cells.

1.3. Functions of melanopsin

Functions that are controlled by photic stimulation of themelanopsin system include the pupil light reflex, circadian pho-toentrainment, sleep regulation, acute suppression of plasmamelatonin, and acute effects of light on cognitive performance,although the expression of these functions varies between humans

K.A. Roecklein et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 229–239 231

Table 1Summary of melanopsin findings in human research.

Authors Year Participants Findings

Thapan et al. 2001 22 Healthy individuals 459 nm light maximally suppressed melatonin releaseBrainard et al. 2001 72 Healthy individuals 446–477 nm most effective in suppressing nighttime melatonin releaseLockely et al. 2003 16 Healthy individuals 460 nm light more effective than 555 nm for phase shift and melatonin

suppressionPhipps-Nelson et al. 2003 16 Healthy individuals 10,000 lx light (fluorescent) reduces subjective sleepiness and improves

psychomotor performance compared to dim 1000 lx (incandescent)Cajochen et al. 2005 10 Healthy men 460 nm light more effective than 550 nm light for melatonin suppression,

alerting response, and responses of body temperature and heart rateZaidi et al. 2007 2 Visually impaired individuals 480 nm peak sensitivity for melatonin suppression, phase shifts, acute increase

in alertness, pupillary constriction, and stimulus detectionAn et al. 2009 12 Healthy individuals 458 nm more effective than 550 nm light for cognitive functioning and arousal

level, 458 nm light produced larger effects at nighttimeRoecklein et al. 2009 130 SAD 90 healthy controls rs2675703 (P10L) T/T variation higher in SAD than controlsGamlin et al. 2007 2 Healthy men Sustained post-stimulus pupilloconstriction (PIPR) maximally sensitive to

482 nmBrainard et al. 2008 26 Healthy individuals 460 nm light optimal for melatonin suppressionMure et al. 2009 12 Healthy individuals Sustained pupil constriction and PIPR maximally sensitive to 460–480 nm,

evidence for melanopsin bistabilityRevell et al. 2010 12 Healthy men 479 nm light more effective for melatonin suppression, but cognitive

performance more sensitive to other wavelengths indicating involvement ofmultiple photoreceptors

Kankipati et al. 2010 37 Healthy individuals PIPR evident in response to 470 nm but not 623 nm stimulusGooley et al. 2010 48 Healthy individuals Melatonin suppression tests indicate that melanopsin is primarily responsive

to long duration, high irradiance stimuliMcDougal and Gamlin 2010 6 Healthy individuals Cone photoreceptors adapt over 30 s, and rods do not respond at high

irradiances, such that long-duration high irradiance stimuli induce melanopsinresponses

Kankipati et al. 2011 16 Glaucoma patients 19matched controls

PIPR lower in glaucoma patients compared to matched controls, PIPR decreasecorrelates with glaucomatous neuropathy

Kardon et al. 2011 32 Retinitis pigmentosa (RP)patients 43 healthy controls

RP patients had a more pronounced PIPR compared to controls

Zele et al. 2011 11 Healthy individuals PIPR maximally evident at CT 15, ∼2 hr 40 min prior to DLMOGagne et al. 2011 10 SAD 10 healthy controls SAD and controls did not differ in ERG after 1 h red or blue stimulus, ERGs

were lower after blue in both groupsGagne and Hebert 2011 12 SAD 11 healthy controls ERG decrease after 10,000 lx 1-hour exposure in summer and winter in SAD

but not controls, did not differ by wavelengthRoecklein et al. 2012 234 Healthy individuals rs2675703 (P10L) T/T variation interacts with photoperiod to predict

chronotype and sleep timing

SAD: seasonal affective disorder. PIPR – post-illumination pupil response. DLMO – Dim light melatonin onset. See Section 3.5 regarding studies on blue or blue-enriched lighttherapy in SAD.

and other mammals. In general, melanopsin knockout mice(Opn4−/−) show impairment in many of these measures, indicatingthat ipRGCs are important for encoding light intensity for ani-mal biological and behavioral responses (Hattar et al., 2003). Someor all of these functions may be relevant to human mood disor-ders, especially the effects on sleep and cognitive performance.Selected findings from the past decade of human research relatedto melanopsin phototransduction and physiology are summarizedin Table 1.

1.3.1. PupillometryThe contribution of melanopsin to neurobehavioral responses

can be distinguished from that of other photoreceptors when expo-sures to specific wavelengths, intensities, and durations of lightare tested. The pupillary light reflex (PLR) adjusts the diameterof the pupil by light intensity, protecting the retina from dam-age and aiding vision. To date, human studies show that blue butnot red wavelengths elicit ongoing constriction during stimulation,ongoing constriction after cessation (i.e., post-illumination pupil-lary response, PIPR), and that the human PLR driven by melanopsinis most sensitive to short wavelength light but may be potenti-ated by longer wavelengths (Gamlin et al., 2007; Kankipati et al.,2010; Kawasaki and Kardon, 2007; Mure et al., 2009). Although inrodents, melanopsin contributes about three times more to steadystate pupil diameter than cones at high irradiances, rods, cones, andmelanopsin cells all contribute to the PLR (Hattar et al., 2003; Lucaset al., 2003; Tsujimura et al., 2010). Although different populations

of melanopsin cells exist, the M1 type intrinsically photosensitiveretinal ganglion cells (ipRGCs) underlie both circadian photoen-trainment and the pupillary light reflex (Schmidt et al., 2011),making it possible to make inferences about the function of onesystem by measuring the other. Pupillometry in humans is a poten-tial tool for investigating “melanopsin-related disorders” (Gamlinet al., 2007). Extended duration stimuli of specific narrow bandwavelengths can be used in a relatively fast and noninvasive wayin human studies to isolate the functioning of melanopsin, allow-ing inferences about the relative sensitivity of melanopsin acrossdiagnostic groups (Do and Yau, 2010; Kardon et al., 2011). Poten-tial clinical applications of pupillometry are broad, from diagnosisof retinal diseases, to possibly discerning the role of melanopsinphotoreception in SAD (Kardon et al., 2011; Wilhelm, 2010).

1.3.2. Circadian photoentrainmentAlthough the etiology of SAD has not been determined, one main

hypothesis contends that SAD is due to a seasonal circadian phasedisturbance, and is discussed more thoroughly below (Lewy et al.,2006). Hence, the role of melanopsin in circadian photoentrain-ment has implications for this hypotheses of SAD. Data indicatethat, in specific conditions of photoentrainment in rodents, about40–50% of the response is driven by melanopsin cells (Do andYau, 2010), although it is unclear if this translates to other non-visual responses in humans. Melanopsin knockout mice, however,have only subtle changes in their circadian rhythms, indicating thatrods and cones convey light information through the melanopsin

232 K.A. Roecklein et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 229–239

ganglion cells for entrainment. Phase shifts in rhythms of humanmelatonin in response to 460 nm light are two-fold greater thanthose in response to 555 nm light at high irradiances, indicatinga primary role of melanopsin photoreception for human circadianphotoentrainment (Lockley et al., 2003).

1.3.3. Melatonin synthesisMelanopsin could also play a role in SAD through the regulation

of melatonin. In both humans and animals, the pineal gland releasesmelatonin at night in response to darkness and signals from thecircadian clock (Lewy, 2007; Nelson et al., 2010). Winter nightsresult in a longer duration of melatonin, which is a biological signalthat triggers seasonal behaviors in mammals, such as changes infeeding and sleeping (Schibler, 2007; Workman and Nelson, 2011).Light acts to acutely suppress melatonin, and mice missing rodsand cones still exhibit suppression of melatonin (Lucas et al., 1999;Panda et al., 2003), implying that melanopsin is involved in acutemelatonin suppression in mice. In humans, short wavelength lightbetween 446–477 nm is the most effective for acute suppressionof melatonin, indicating a primary role for melanopsin in mela-tonin suppression (Brainard et al., 2001; Revell et al., 2010; Thapanet al., 2001). Cone photoreceptors, in addition, appear to contributeto human melatonin suppression at the beginning of light expo-sure (Gooley et al., 2010). Both early and late responses to light inhumans may be therapeutically important, and optimal light ther-apy might employ both longer and shorter wavelengths to engagecones as well as melanopsin (Brainard et al., 2001, 2008; Gooleyet al., 2010; Revell et al., 2010; Thapan et al., 2001).

1.3.4. Circannual rhythmsMany rhythms that recur annually, such as in the seasonally

breeding Siberian hamster, are driven by changes in day lengthand the resulting increase in the duration of nightly melatonin syn-thesis (see Schibler, 2007 for a review). In addition to melatonin,other circadian markers of season that may also be influenced bymelanopsin-mediated light input include photoperiod-dependentpatterns of gene expression in rodents (Sumova et al., 2003;Tournier et al., 2003; Travnickova et al., 1996) and seasonal varia-tions in the electrophysiological activity in the rodent central clockthat encode day length (VanderLeest et al., 2007). Given the roleof melanopsin in melatonin and circadian entrainment describedabove, seasonal rhythms driven by circadian rhythms or photope-riod would be similarly dependent on individual differences inmelanopsin functioning. In healthy humans, controlled laboratorystudies have shown that the melatonin rhythm as well as prolactin,cortisol, body temperature and sleep are influenced by photoperiodlength (Wehr, 1991; Wehr et al., 1993). Those studies illustrated theconservation of photoperiodic responsiveness of humans, althoughit has been suggested that in industrialized societies, photoperiodicresponses may be masked by higher ambient artificial light levelsWehr et al., 1993). In contrast, one study found no seasonal changein the nightly duration of melatonin release in controls, suggestingthat only some subgroups of individuals, notably those with SAD,retained the lengthened duration of melatonin release seen in othermammals (Wehr et al., 2001).

1.3.5. Sleep regulationSince hypersomnia is a primary SAD symptom, the role of

melanopsin in sleep regulation may be important. Extensive humanresearch has established that light has clear effects on (1) circa-dian entrainment of sleep, (2) homeostatic sleep regulation, and (3)acute light-induced effects on alertness. Animal research indicatesthat melanopsin plays a role in some or all of this sleep regula-tion and physiology. Melanopsin cells project to neural regionsinvolved in sleep regulation (Hattar et al., 2006) including the ven-tral lateral pre-optic area (VLPO; Hannibal and Fahrenkrug, 2004;

Lu et al., 2000), and the superior colliculus (SC), which has beenimplicated in the photic regulation of sleep (Gooley et al., 2003;Miller et al., 1998). In nocturnal rodents, light during the darkactivity phase will acutely induce sleep, but in diurnal animalsand humans, short wavelength light has the expected oppositeeffect of increased alertness. Knockouts, however, have signifi-cantly reduced acute light-induced activation of the VLPO and SC,and do not exhibit acute sleep responses to light, or experience adelay in such responses (Altimus et al., 2008; Do and Yau, 2010; Lupiet al., 2008; Tsai et al., 2009). Melanopsin appears to be involvedin the physiological basis of the homeostatic sleep drive, sincemelanopsin knockout mice exhibit reduced sleep duration and debt(Tsai et al., 2009).

1.3.6. AlertnessDecrements in alertness are also relevant for depression,

although light has the opposite effect on nocturnal mice as indiurnal humans. In mice, darkness is alerting during the lightphase, but this effect is delayed in melanopsin knockouts, indicatingthat melanopsin participates in driving acute alertness responses(Altimus et al., 2008; Tsai et al., 2009). These data lead to thehypothesis that a melanopsin-mediated effect on alertness mayexplain the role of melanopsin in SAD (Schmidt et al., 2011). Humanstudies have found that light causes an acute increase in cognitiveperformance and alertness (e.g., Badia et al., 1991; French et al.,1990), especially short wavelength light (An et al., 2009; Cajochenet al., 2005; Lockley et al., 2006; Phipps-Nelson et al., 2003; Revellet al., 2010; Zaidi et al., 2007; Figueiro et al., 2007). Based onspectral sensitivity, however, self-reported alertness ratings aredriven by a combination of photoreceptors whose contributionsmay vary across the day (An et al., 2009; Revell et al., 2010).Although light may increase alertness by suppressing melatoninwhen it is released, other as yet unidentified process stimulatingthe ascending arousal system and cortex are likely during the daywhen melatonin is low (Lockley and Gooley, 2006).

1.3.7. Daily rhythmDaily variations in melanopsin cell numbers, protein, and mRNA

have been observed in animals (Gonzalez-Menendez et al., 2009;Hannibal et al., 2005; Sakamoto et al., 2004), although dailyvariations in melanopsin-related functions may also be due todownstream processes in the melanopsin and circadian pathways.In humans, it appears that a daily variation in the sensitivity ofthe melanopsin pathway occurs, as reflected by the PIPR (Zeleet al., 2011), and melatonin suppression and iris constriction(Figueiro et al., 2005). Objective measures of human cognitivefunction in response to light are highest at night, after dusk (Anet al., 2009). The mechanism behind such daily variation is likelyto be due to an interaction between multiple photoreceptors, theclock, and light input (Dacey et al., 2005; Wong et al., 2007). Forexample, the peak period of melanopsin mRNA expression in ratsincreases in duration under long day length conditions and is illu-mination dependent (Mathes et al., 2007). It is possible that a lightsensitive transcription feedback loop controls melanopsin activity(Hannibal et al., 2005), such that the effect of light on circadian,neuroendocrine and neurobehavioral processes varies by time ofday. Consistent timing of measurement is therefore critical whenstudying behavioral responses dependent on melanopsin.

2. SAD etiology

Although biological hypotheses of SAD have been reviewed else-where (Lamont et al., 2007; Levitan, 2007; Rohan et al., 2009),none have yet incorporated the recent findings regarding thesemelanopsin-containing ganglion cells that regulate the biologicaland behavioral responses to light. Seasonal changes in circadian

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rhythms and light responses in humans and animals can be healthyor adaptive, but individuals with SAD may experience a patho-logical extreme of normal human seasonal variation (Magnusson,2000). In seasonally breeding rodents, multiple biological rhythmsvary across the seasons, and such rodents may have utility as poten-tial animal models for SAD (Workman and Nelson, 2011). There isevidence of seasonal variation in humans such as seasonal peaksin birth rates, growth rate, cortisol, testosterone, pain thresholds,alertness, sexual activity and conception, and behaviors such ascrime, suicide, all cause mortality, and rape (see Roenneberg andAschoff, 1990; Lam and Miron, 1991; Workman and Nelson, 2011).Aschoff (1981) suggests that sociocultural factors and increasingindustrialization may explain a decrease in amplitude of these sea-sonal rhythms since the 1930s. The general U.S. population reportsa winter worsening of mood, increased appetite, longer sleep dura-tion, and decreased energy and social interaction levels in winter(Rosen et al., 1990). SAD is seen as the extreme case on a continuumof seasonal variations in mood and behavior (Kasper et al., 1989).In fact, some degree of seasonal depression may have once beenadaptive as a means to save energy in winter, although wintertimedecrements in activity would be less adaptive in our current envi-ronment (Eagles, 2004). Here we describe etiological hypotheses ofSAD, with a focus on the possible role of melanopsin in many of thehypotheses.

2.1. Circadian hypotheses of SAD

2.1.1. Phase shift hypothesisThe phase shift hypothesis proposes that SAD occurs when circa-

dian rhythms are out of phase, shifted earlier or later, relative to thesleep/wake cycle (Lewy, 2007). This hypothesis has been defined asthe difference between a marker of circadian phase (i.e., DLMO) andmid-sleep, or a misalignment in the phase angle between the cir-cadian clock and the sleep/wake cycle. Although a majority (71%)of SAD patients have delayed rhythyms (Lewy et al., 2006), approx-imately half do not have significantly different rhythms comparedto controls (46%; Eastman et al., 1993). This indicates that circa-dian misalignment alone may not explain SAD etiology. Morninglight therapy (or combined morning/evening light) appears supe-rior to evening or midday light therapy administration (Termanet al., 1989). When circadian misalignment is measured, treatmentto correct misalignment is associated with decreased depressionsymptoms in SAD (Lewy, 2007), and the degree of change in mis-alignment is associated with degree of improvement (e.g., Lewyet al., 2006). It may be that subgroups of individuals with SAD havedifferent directions and degrees of misalignment, perhaps due todifferent genetic predispositions. Given the role of melanopsin incircadian entrainment, and this evidence for circadian misalign-ment in SAD, it is not surprising that melanopsin gene variations areassociated with changes in sleep timing and chronotype (Roeckleinet al., 2012), although these findings have not yet been replicated.

2.1.2. PhotoperiodThe photoperiod hypothesis of SAD states that longer duration

of nocturnal melatonin release, due to longer nights in winter,may be a “circadian signal of change in season,” triggering depres-sion (Wehr et al., 2001). Wehr et al. (2001) tested the photoperiodhypothesis in SAD and healthy controls living in their usual envi-ronment. Individuals with SAD had longer winter melatonin release(30–48 min in men and women compared to themselves in sum-mer), a seasonal variation not seen in healthy controls (Wehr et al.,2001). Individuals with SAD did not have a significant phase shiftcompared to healthy controls in winter, but time of melatonin off-set and midpoint was consistent with the phase shift hypothesis(Wehr et al., 2001). It remains to be seen if regular light therapy dur-ing winter can lead to shortened duration of melatonin release in

SAD, or if gene variations are associated with melatonin. In healthyindividuals, there can be large individual differences in nighttimeacute suppression of melatonin by light (Brainard et al., 1988). Fur-ther, evening melatonin suppression by light is more effective inwinter (Owen and Arendt, 1992). Although the factors explainingthese seasonal and individual differences in light suppression ofmelatonin are unknown, one possible explanation could be genet-ically mediated differences in retinal sensitivity.

2.1.3. Retinal sensitivityThe retinal subsensitivity hypothesis proposes that normal

increases in retinal sensitivity in response to low light levels inwinter is impaired, leading the retina to be less sensitive thannecessary (Hebert et al., 2002; Reme et al., 1990). Whole retinarecording measures include electroocculography (EOG), and elec-troretinography (ERG), under either scotopic conditions, reflectingprimarily rod responses, or photopic conditions, reflecting largelycone driven responses.

2.1.3.1. Electroocculography. Two studies found lower EOG ratiosin SAD, which would reflect lower electrical potential and activityif outside of the normal range (Lam et al., 1991; Ozaki et al., 1993).The first study to analyze season found that healthy individuals hadhigher EOG ratios in winter compared to summer, a difference notseen in SAD patients (Ozaki et al., 1995). This indicates that the up-regulation thought to be required for low winter light levels wasnot occurring in SAD, and that the lack of up-regulation could bepathological in SAD. In SAD patients responding to one week ofwinter light therapy, however, low EOG ratios did not rise to thelevels seen in controls (Ozaki et al., 1993). The underlying mecha-nism behind EOG levels is still unclear, making conclusions difficultto draw from this type of recording.

2.1.3.2. Electroretinography. One study using scotopic ERG inresponse to dim white light flashes found that women with SAD hadlower ERG, but men with SAD had higher ERG amplitude comparedto controls, while other studies did not find this gender difference(Lam et al., 1992). Both individuals with subsyndromal seasonalaffective disorder (S-SAD) (Hebert et al., 2002) and SAD (Hebertet al., 2004) had lower rod sensitivity (i.e., scotopic ERG) in win-ter compared to controls. This difference normalized in summerand after treatment with light therapy (Hebert et al., 2004). Thephotopic ERG may also be decreased in SAD in winter, and doesnot differ from controls after light therapy or in summer (Lavoieet al., 2009). Recently, SAD and control participants were exposedto 10,000, 100, and 5 lx light for one hour (Gagne and Hebert, 2011).A significant decrease in ERG following 10,000 lx 1 h exposures wasfound in both summer and winter in SAD but not controls, and isproposed as a biomarker of SAD, although the response was not spe-cific to wavelength. In a recent study using different wavelengths,ERGs were compared between SAD and control participants aftereither a red or blue 1 h exposure (Gagne et al., 2011). ERGs weresignificantly lower after the blue stimuli, but SAD and controls didnot differ. There may be other measures, such as chromatic pupil-lometry (e.g., the PIPR, which is primarily driven by melanopsincontaining cells and not rods and cones), that are more sensitiveto melanopsin cell functioning than ERG, given that melanopsincells are only 1–2% of the ganglion cells in the retina (Provencioet al., 1998) and would contribute less to whole retina recor-ding responses like ERG. Considering synaptic connections throughbipolar cells from both rods and cones to the M1 (melanopsin type1) cells involved in the pupillary light reflex and circadian photoen-trainment (Schmidt et al., 2011), it stands to reason that deficits inthe classical photoreceptors would impact melanopsin-mediatedfunctions as well.

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2.1.4. SleepMost individuals with SAD (80%) report hypersomnia (Kaplan

and Harvey, 2009). Despite reports of hypersomnia, studies havenot been able to identify changes in sleep architecture and sleepregulation specific to SAD. Although some studies find no differ-ences in homeostatic drive, some evidence suggests a deficiencyin the homeostatic drive in SAD (Cajochen et al., 2000). Reportsof hypersomnia may also reflect a desire for more sleep as aresult of disrupted sleep (Kaplan and Harvey, 2009). When mea-sured actigraphically, individuals with SAD had decreased sleepefficiency, daytime inactivity, greater time in bed, and a phase-delay compared to healthy controls, but showed no increase inactual time spent asleep (Winkler et al., 2005). Home actigraphyand/or polysomnography may help distinguish increased time inbed from increased total sleep time in those reporting hypersom-nia (Kaplan and Harvey, 2009). Another important aspect of sleepin SAD may be the timing of sleep, and resultant effects on circa-dian phase. In healthy individuals, sleep durations of 9 h and latermorning wake times (3 h later) led to a significant phase delay in thetiming of dim light melatonin onset (Burgess and Eastman, 2006).When healthy individuals in the same study slept 6 h and woke attheir regular workday time, a phase advance was observed, indi-cating the importance of morning wake time and light exposurefor circadian entrainment. Perhaps individuals with SAD are mostsimilar to those in the 9 h sleep condition, and are phase delayed asa result, suggesting an interaction between circadian entrainmentand sleep.

2.1.5. NeurotransmittersThe role of neurotransmitters including serotonin and dopamine

(DA) has been investigated in SAD. Variations in DA related genes,such as the D4 receptor gene variation (DRD4 VNTR), are associatedwith SAD, specifically with eating behavior, carbohydrate craving,and body mass index (Levitan et al., 2004, 2006). Because DA isadditionally involved in modulating retinal sensitivity and neuro-biological responses to light, it is possible that SAD etiology could beexplained by variations in dopaminergic signaling (Levitan, 2007),independently of melanopsin phototransduction. Future studiesmay investigate an association between reduced ERG in SAD, asdescribed above, and the DRD4 variation in SAD (Levitan, 2007).More complex interactions between DA, melanopsin, and reti-nal sensitivity are possible given that DA is involved in light anddark adaptation in the retina (Levitan, 2007; Witkovsky, 2004),melatonin can inhibit DA release, and DA can inhibit melatonin pro-duction in the retina (Cahill and Besharse, 1991). DA agonists in theretina cause increased melanopsin mRNA expression (Sakamotoet al., 2005), suggesting the possibility that DA variations mayimpact melanopsin signaling through regulation of OPN4 mRNAexpression. DA also may modulate ipRGC signaling (Van Hook et al.,2012), and ipRGCs appear to project to dopaminergic intraneu-rons in the retina, thereby contributing to visual signaling (Zhanget al., 2012). Hypodopaminergic states in the retina could changeDA mediated signaling in cones (Witkovsky, 2004), and given thecontribution of cone signaling to melanopsin containing ganglioncells (Schmidt et al., 2011), it is theoretically possible that DAgene variations could impact melanopsin cell functioning throughcone-driven processing. Although disruptions in serotonergic neu-rotransmission are likely to represent an underlying vulnerabilityin SAD (e.g., Neumeister et al., 2001), it is less likely that serotoninwould interact with melanopsin signaling or retinal sensitivity. Theneurotransmitter hypothesis of SAD has been well described else-where (Neumeister et al., 2001).

2.1.6. HyperphagiaIndividuals with SAD are more likely to report increased

appetite, food intake (i.e., hyperphagia), weight gain, and

carbohydrate craving. Further, 17–26% of those diagnosed withSAD present with a comorbid eating disorder diagnosis, partic-ularly Bulimia Nervosa (BN) (Lam et al., 2001). Interestingly, inwomen with comorbid SAD and BN, light therapy led to a decreasein binge/purge episode frequency, but was more effective in alle-viating mood symptoms (Lam et al., 2001). Although light therapymay improve mood, which in turn decreases eating symptomology,it is also possible that increased light levels directly affect eatingbehavior through modulation of hypothalamic pathways involvedin metabolic and energy homeostasis or via circadian physiology.Neuroanatomical studies have demonstrated that melanopsin cellsproject to the lateral hypothalamus, a region involved in regulatingenergy homeostasis, suggesting that light may have direct effectson eating and/or metabolism (Hattar et al., 2003).

2.1.7. InteractionsIndividual differences in light sensitivity could be a function of

retinal sensitivity, the sensitivity of the circadian clock to light,reduced light input, or a combination of these factors. Circadianvariations in the sensitivity of melanopsin signaling are likely toreflect a complex feedback loop between central and retinal clocks(Hastings et al., 2003; Zele et al., 2011). For example, an individ-ual with SAD may have decreased melanopsin sensitivity, whichmay only be an issue in winter when environmental light levelsare lower and input is decreased. The complexity of the systemis increased considering that environmental factors interact withbiological factors.

2.2. Environment

The environmental trigger for SAD is most likely the changein the daily light/dark cycle due to a change in season or latitude(Rosenthal et al., 1984). The temporal sequence of symptom onsetin SAD is most closely linked to photoperiod than other climaticvariables (e.g., minutes of sunshine, global radiation, cloud cover;e.g., Young et al., 1997). In England, not only are actimetrically-measured light levels higher in summer overall, but evening bluelight is 3 times higher in summer compared to winter (Thorne et al.,2009). Research shows that individuals with SAD, however, receivethe same amount of winter light compared to controls (Guillemetteet al., 1998), and more in summer compared to controls (Grawet al., 1999). Therefore, individuals with SAD may be more sen-sitive to seasonal changes in natural light decreases in winter, ormore vulnerable to this natural seasonal change (Guillemette et al.,1998).

2.3. Summary

Given the reliance of circadian, neuroendocrine and neuro-behavioral physiology on environmental light, and the roles ofthese functions in SAD, we hypothesize that winter environmen-tal light input triggers a susceptibility to low light levels. Sinceall individuals living at high latitudes are exposed to seasonalchanges in photoperiod, predispositions must explain why onlysome develop SAD. Future research is needed to determine if abnor-mal retinal sensitivity may constitute year-round or winter-onlychanges in retinal sensitivity, or it may be that certain individ-uals are less sensitive to RHT input centrally. One possibilityis that low light levels in the winter may fall below a thresh-old in either melanopsin-specific, or general retinal sensitivity,which is required for euthymic functioning. Such a threshold maybe biologically mediated by individual differences in the circa-dian photoreceptor system as a whole, or melanopsin functioningspecifically. Such individual differences in retinal sensitivity mayhave consequences for central nervous system targets involved incircadian, neuroendocrine and neurobehavioral functions, leading

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Table 2Summary of future directions in research.

Study descriptionsPupillometry designed to isolate the sensitivity of melanopsin cells (i.e.,Post Illumination Pupil Response; PIPR)

Consider time of assessment, circadian phase of participant, seasonand/or photoperiod

Adjust for age-related changes in lens densityReview methodological considerations (Wilhelm, 2010)Carefully chose duration, intensity (irradiance) and wavelength given

specific experimental questionsEvaluate the blue-light hazard over the duration of exposure typical inlight therapy for SADTest whether pupillometry or variations in genes involved in circadianentrainment can predict response to light therapyDetermine if long wavelengths prior to broad-spectrum light therapy canpotentiate response in light therapy

Notes: See Section 3 for elaboration.

to symptoms typically seen in SAD such as sleep and eating changesas well as circadian phase shifts.

3. Future directions

The potential relationship between melanopsin, light, and SADhas been under-explored, in general. Table 2 details the follow-ing recommendations for areas of future research. With our recentand growing understanding of melanopsin containing ipRGCs, andthe hypothesis for how melanopsin may play a role in seasonaldepression, the next step is to describe a method of action forassessing the model with hypothesis testing. To date, much of theresearch on melanopsin physiology, especially as it might relateto seasonal variations, has been on healthy animals, and healthyhumans, and very little in SAD, highlighting the need for futurestudies in healthy humans, those with SAD, and possibly in ani-mal models of SAD (Workman and Nelson, 2011). Importantly,the contributions of ipRGCs to mood in humans, or animal mod-els of depression, have not yet been described at the level of detailknown for other ipRGC contributions (Schmidt et al., 2011). In test-ing whether or not melanopsin photoreception mediates seasonalvariations in responses to light in SAD, critical issues include thenature of light stimuli, measurement of responses, and study designissues. Specifically, pupillometry designed to isolate the sensitivityof melanopsin cells from rods and cones, which has been employedin studies of retinal pathology, may lead to breakthroughs in ourunderstanding of SAD.

3.1. Methodological considerations

Variables to consider in pupillometry include time of assess-ment, patient age, stimulus background and intensity, eye ofexposure versus recording, sufficient spatial and temporal resolu-tion in pupillometry recording equipment, and careful analysis ofoutcome data including appropriate handling of amplitude, blinks,and multiple observations per participant (Wilhelm, 2010). In addi-tion, factors affecting the autonomic nervous system such as noise,arousal level, cognitive load, and medications should be controlled(Markwell et al., 2010). The effect of light stimuli on the retinacan be affected by head movements, blinks, pupil constriction,and light transmission through the ocular media (Brainard et al.,1997, 2001; Gaddy et al., 1993). As the human lens ages, trans-mission of short wavelengths of light is reduced (Brainard et al.,1997; Lerman, 1987), so efforts to control for these age effectsare necessary. Given that the sensitivity of the human visual sys-tem differs from the circadian system, it is currently more usefulto quantify irradiance or photon density within a specified bandof wavelengths rather than illuminance (An et al., 2009; Brainard

Fig. 1. Responsitivity of melanopsin compared to other photopigments. Notes: Logrelative sensitivity scaled to fit an A1-based photopigment nomogram identifying482 nm as the wavelength at which melanopsin-containing ganglion cells are mostsensitive in the non-human primate. S – short, M – medium, and L – long wavelengthcone cells.

Reprinted by permission from Macmillan Publishers Ltd: Nature, (Dacey et al., 2005),copyright (2005).

et al., 2001; Gooley et al., 2010). Illuminance measures reflect thewavelength sensitivity of the human visual system to light and cansignificantly misrepresent photic input for nonvisual responses. Anumber of nascent models have proposed a basis for light measure-ment related to circadian, neuroendocrine and neurobehavioralresponses. For example, the recently described “melanopic” photo-metric measure of light intensity predicts melanopsin-driven pupiland circadian responses to polychromatic light in mice with onlyipRGC photoreceptors (rd/rd cl mice; Enezi et al., 2011).

3.2. Chromatic pupillometry

Because current measures of retinal function like ERG measureelectrical activity across the entire retina, the effect of relativelysparse melanopsin cells may be quite low unless stimuli are care-fully designed to reflect melanopsin responses. For example, thepost-illumination pupil response (PIPR) is likely to be predomi-nately mediated by melanopsin cells as opposed to rods or cones,leading to methods designed to elicit melanopsin responses (Parket al., 2011). Studies using monochromatic light stimuli may wantto approach 460 nm as opposed to 480 nm to optimally stimulatemelanopsin-driven responses, as 460 nm is the wavelength maxi-mally driving sustained melanopsin driven pupil responses to longduration stimuli (McDougal and Gamlin, 2010; Mure et al., 2009),as well as prolonged exposures for acute melatonin suppression(Brainard et al., 2001; Thapan et al., 2001). The spectral profile ofphotoreceptors (i.e., rods, cones, and ipRGCs) in the primate retinais shown in Fig. 1, demonstrating that narrow bandwidth stimuliare needed to minimize “bleed-through” of a stimulus intended tostimulate only ipRGCs. In SAD, it is more likely that sustained lightinput, from the environment across the day, is more etiologicallysignificant than brief stimuli. In addition, it may be more ecolog-ically valid to use polychromatic light stimuli when evaluatingcircadian, neuroendocrine and neurobehavioral responses. Finally,cones appear to provide strong early input and subsequently adapt,while melanopsin cells provide sustained input during continuousillumination without evidence for adaptation (Dollet et al., 2010;Gooley et al., 2010). In mice, rods appear to play a large role in

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circadian photoentrainment, in addition to cones, so it is importantto consider rod contributions when trying to isolate the responsesof ipRGCs (Altimus et al., 2010).

3.3. Assessment timing

Beyond careful control of stimuli parameters, the timing of lightexperiments is critical because of the existence of circadian varia-tions in melanopsin cell sensitivity. As described above, melanopsincells display a daily variation in a number of factors that may affectsensitivity (Gonzalez-Menendez et al., 2009; Hannibal et al., 2005;Sakamoto et al., 2004; Zele et al., 2011). It is not yet known ifefforts to standardize timing across participants should be basedon the timing of first light exposure at awakening, or based on cir-cadian time. Each would imply different means of controling forvariables known to influence melanopsin functioning including cir-cadian time, previous light exposure, and current environmentalphotoperiod.

3.4. Blue light hazard

Concerns have been raised about the safety of both experimen-tal and therapeutic light exposures (Gagne et al., 2011; Reme et al.,1996; Terman, 2009). Since light devices vary in their spectral com-position, it is always prudent to assure light dosages given to thehuman eye fall within safe exposure limits. According to nationaland international standards, one of the defined risks of photochem-ical retinal injury, the blue light hazard, is highest between 400 and500 nm (ACGIH, 2010; ANSI, 2005, ICNIRP, 1997). Researchers canuse the published standards to calculate the safe limit of durationand irradiance for stimuli (Brainard et al., 2001, 2008; Glickmanet al., 2006; West et al., 2011). Values for absolute irradiance andwavelength of a light source can be determined with a spectropho-tometer. Measured irradiance then should be integrated using ablue-light hazard weighting function. Standards are based on expo-sure durations from 1 ns to 8 h (ACGIH, 2010; ANSI, 2005, ICNIRP,1997). Since light therapy for SAD is typically used daily during falland winter for 30–60 min, it is within the dosimetric range of thesestandards. Absolute irradiance measurements also permit experi-menters to determine the photon density at each wavelength froma light source, critical for accurately interpreting the physiolog-ical, behavioral and therapeutic responses to light (Revell et al.,2010). Hence, it is important for SAD researchers to provide detailon the spectrum and irradiance of their light sources (Andersonet al., 2009; Revell et al., 2010; West et al., 2011).

3.5. Optimizing light therapy for SAD

The discovery and characterization of the melanopsin path-way triggered interest in using lights with wavelengths centeredaround the blue portion of the visible spectrum, or broad bandwidthlight with increased intensity in the blue-appearing wavelengths.Studies have established that blue or blue-enriched lights at signifi-cantly lower light irradiances, yield similar rates of improvement inSAD as traditional bright white light therapy units (Anderson et al.,2009; Glickman et al., 2006; Meesters et al., 2011; Strong et al.,2009), and are able to phase advance rhythms (Smith et al., 2009).Outstanding questions include whether the melanopsin cells areprimary in mediating light therapy’s effects, and whether it maybe possible to potentiate the effects of light therapy by using longwavelength light first (Gooley et al., 2010; Mure et al., 2009; Rollag,2008). Furthermore, it is possible that gene variations could be usedto predict the timing, duration, risk of side effects, and potentialbenefit of light therapy, opening the door to individualized treat-ment prescriptions in the future.

3.6. Conclusions

The new research on melanopsin and the circadian, neuroen-docrine and neurobehavioral repsonses to light has providedan opportunity to understand the physiology behind individualdifferences in responses to seasonal changes in light levels. Itappears that melanopsin sequence variations may increase risk formood disorders with a seasonal pattern. Further, seasonal vari-ations in sleep and chronotype may be mediated by differentthresholds of melanopsin-based sensitivity to light. Both of theseSNP-association studies, however, deserve replication. Determin-ing if the melanopsin pathway is involved in mood and sleepdisorders may help improve treatment outcomes by determiningthe time, duration, and wavelength for optimal light therapy. Inaddition, it may be possible to identify subgroups of individualswith SAD for whom melanopsin functioning may or may not beimportant, allowing for individually tailored treatment prescrip-tions.

Acknowledgements

Development of this manuscript was primarily supportedby 1R03MH096119-01A1 to Kathryn A. Roecklein, Ph.D. GeorgeBrainard, Ph.D. was supported, in part, by the National SpaceBiomedical Research Institute through NASA NCC 9-58 and TheInstitute of Integrated Health. Dr. Brainard is the inventor or co-inventor on three patents: USPTO Patent Serial No. 09/853,428;USPTO active continuation application No. 12657533; and pendingWorld PCT 2005/004948AZ.

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